Lamivudine and Emtricitabine Dosing Proposal for Children with HIV and Chronic Kidney Disease, Supported by Physiologically Based Pharmacokinetic Modelling

Tom G. Jacobs*, Marika A. de Hoop-Sommen, Thomas Nieuwenstein, Joyce E.M. van der Heijden, Saskia N. de Wildt, David M. Burger, Angela Colbers, Jolien J.M. Freriksen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Dose recommendations for lamivudine or emtricitabine in children with HIV and chronic kidney disease (CKD) are absent or not supported by clinical data. Physiologically based pharmacokinetic (PBPK) models have the potential to facilitate dose selection for these drugs in this population. Existing lamivudine and emtricitabine compound models in Simcyp® (v21) were verified in adult populations with and without CKD and in non-CKD paediatric populations. We developed paediatric CKD population models reflecting subjects with a reduced glomerular filtration and tubular secretion, based on extrapolation from adult CKD population models. These models were verified using ganciclovir as a surrogate compound. Then, lamivudine and emtricitabine dosing strategies were simulated in virtual paediatric CKD populations. The compound and paediatric CKD population models were verified successfully (prediction error within 0.5- to 2-fold). The mean AUC ratios in children (GFR-adjusted dose in CKD population/standard dose in population with normal kidney function) were 1.15 and 1.23 for lamivudine, and 1.20 and 1.30 for emtricitabine, with grade-3- and -4-stage CKD, respectively. With the developed paediatric CKD population PBPK models, GFR-adjusted lamivudine and emtricitabine dosages in children with CKD resulted in adequate drug exposure, supporting paediatric GFR-adjusted dosing. Clinical studies are needed to confirm these findings.

Original languageEnglish
Article number1424
JournalPharmaceutics
Volume15
Issue number5
DOIs
Publication statusPublished - 6 May 2023

Bibliographical note

Funding Information:
AC received honoraria from Merck Sharp & Dohme Corp and Gilead, paid to the institution. AC received study grants from Merck Sharp & Dohme Corp, Gilead, and ViiV Healthcare, paid to their institution. SW received honoraria from Khondrion, paid to institution. SW, MHS, JF, and JH receive research funding from the Bill and Melinda Gates Foundation (paid to institution). SW is the Director of the Dutch Pediatric Formulary. All other authors declare no conflicts of interest.

Funding Information:
Considering the authors M.H.S., J.V.D.H., S.N.W. and J.F.: This publication is based on research funded by the Bill and Melinda Gates Foundation (INV-001822). The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill and Melinda Gates Foundation.

Publisher Copyright:
© 2023 by the authors.

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